Approximately every ten seconds, a person dies of tuberculosis somewhere in the world. Tuberculosis is the world's number one killer among infectious diseases and the leading cause of death among women of reproductive age. Although developing countries bear the greatest burden of disease, the United States is greatly affected by tuberculosis, reporting 16,377 cases in 2000.
The infectious agent causing almost all cases of tuberculosis is Mycobacterium tuberculosis (M. tuberculosis). M. tuberculosis is easily spread between individuals through the air. A single cough by an infected individual can generate as many as 3000 infected droplet nuclei, while less than 10 bacilli may initiate a pulmonary infection in a susceptible individual. Because simply inhaling an airborne pathogen may infect individuals, tuberculosis outbreaks are difficult to contain and require isolating the infected individuals in negative air pressure rooms.
Although it was believed that tuberculosis would eventually be eliminated after the development of antibiotics in the 1950s, in 1999, tuberculosis was labeled as a global health emergency by the World Health Organization. One of the major reasons for the perseverance of tuberculosis is the evolution of multi-drug resistant strains. Multi-drug resistant strains have evolved in part due to infected patients' poor compliance with drug therapy, which lasts for a period of at least six months. One multi-drug resistant strain, strain W, has evolved resistance to all first-line drugs (isoniazid, rifampin, ethambutol, and pyrazidine), as well as one second-line drug (kanamycin). It is therefore evident that tuberculosis continues to be a serious health threat to individuals worldwide.
Initial infection with M. tuberculosis only rarely leads to immediate disease because the infection is typically controlled by the host's immune system. Among people infected with M. tuberculosis, approximately 5% manifest the disease within a few years after infection. Upon initial infection, the mycobacteria enter unactivated macrophages and multiply therein. Following a rapid growth phase, infected macrophages and their bacilliary cargo are surrounded and walled off by newly recruited activated macrophages. This walling off of the infected macrophages results in the characteristic granuloma. The granuloma is a compact, organized collection of activated macrophages, including epithelioid and multinucleated giant cells; surrounded by T lymphocytes, and later by fibroblasts and collagen, which aggregate around the macrophage core.
Mycobacterial dormancy results in a disease stage termed latent tuberculosis. An individual with latent tuberculosis may later develop a case of reactivated tuberculosis, and in fact, the majority of the tuberculosis cases reported in the United States are the result of reactivation of a mycobacterial infection and not an initial infection. (Am. Rev. Respir. Dis. 146:1623–1633, 1992). Reactivation of the M. tuberculosis bacilli usually occurs in the apex of the lung where large numbers of tubercle bacilli cause necrosis of the small bronchi of the lung. The characteristic bloodstained sputum of tuberculosis results from the erosion of small blood vessels during this necrotic process.
Approximately one-third of the population worldwide has been estimated to be latently infected with M. tuberculosis. (Sudre et al., Bull. W.H.O. 70:149–159, 1992). Currently, the tuberculin skin test is the only available diagnostic for those infected with M. tuberculosis. Unfortunately, no currently available test can specifically identify latently infected individuals. The tuberculin test is only capable of identifying all individuals either exposed to the pathogen or vaccinated against the pathogen. Due to the high number of latently infected individuals and the risk of reactivation of tuberculosis in those individuals, diagnostics and therapeutics targeted to latent tuberculosis need to be developed. In addition, the development of an in vitro granuloma model for the study of mycobacteria and for the development of tuberculosis drug and vaccine candidates would be desirable.